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Year 2 - Muscoloskeletal > MBD - Biochemistry > Flashcards

MBD - Biochemistry Flashcards

1
Q

• Define MBD

A

Metabolic Bone Disease:

A group of diseases that cause a change in BONE DENSITY and BONE STRENGTH by:
• Increasing bone reabsorption
• Decreasing bone formation
• Altering bone structure (and may be associated with disturbances in mineral metabolism)

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2
Q

5 most common MBDs and its symptoms?

A
  • 1o hyperparathyroidism
  • Rickets/Osteomalacia
  • Osteoporosis
  • Paget’s
  • Renal osteodystrophy

Symptoms:
o Metabolic
– hypo/hyper-calcaemia
– hypo/hyper-phosphataemia

o Bone
– bone pain
– deformity
– fractures

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3
Q

Explain bone calcium

A

Hydroxyapatite

Cancellous (trabecular) bone is metabolically active
– with 5% remodelling at any one time
– continuous exchange of ECF with the bone fluid reserve

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4
Q

What makes a bone strong?

A

Strong by:
• mass
• material properties (e.g. cross-linked collagen)
• microarchitecture (e.g. trabecular thickness)
• macroarchitecture (e.g. hip axis length)

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5
Q

What is the structure & function of bone assessed by?

A

• Bone histology
• Biochemical tests
• Bone mineral densitometry (e.g. osteoporosis)
Radiology

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6
Q

Explain age-related changes in bone mass

A

o Men and women tend to reach the “consolidation” stage at 28yo and the lose bone mass past 42yo.

o Menopause makes women pass the fracture threshold whilst many men never go below it.

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7
Q

How do men and women form new bone and what can change the shape of bone?

A

 Sexual dimorphism
– men have appositional bone growth whilst women form new bone on the inside of the bone marrow

 Growth and exercise can change the shape of bone.

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8
Q

Explain what Micro-Fractures are and how they can form

A

Cracks occur between OSTEONS which is the reason for constant bone remodelling (5% at any one time).

  1. Osteoclasts reabsorb damage
  2. Osteoblasts lay down new bone.
  3. Osteoblasts absorbed in laying down bone, act as mechanoreceptors for future fractures.
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9
Q

What are the biochemical investigations that can be undertaken in bone disease?

What 3 main systems are involved in Ca2+ balance?

A 
SERUM:
• Bone profile:
 - Ca2+,
 - corrected Ca2+ (albumin)
 - phosphate
 - ALP
• Renal Function:
 - creatinine
 - PTH
 - 25-OH VitD

URINE:

  • Ca2+/PO43+
  • NTX

Ca2+ balance involves the GI tract, kidneys & the bone - 3 MAIN SYSTEMS

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10
Q 
Give the biochemical changes seen in bone disease in each of the 5 MDBs & metastases
\:
 Ca
 P
 Alk P
 Bone form
 Bone resorpt
A 
Osteoporsis:
 • Ca = N
 • P = N
 • Alk P = N
 • Bone form = INCREASE then steady
 • Bone resorpt = INCREASE
Osteomalacia:
 • Ca = N or DECREASE
 • P = DECREASE
 • Alk P = INCREASE
 • Bone form = n/a
 • Bone resorpt = n/a
Pagets:
 • Ca = N (or increasE)
 • P = N
 • Alk P = INCREASE
 • Bone form = INCREASE 
 • Bone resorpt = n/a
1o HPT:
 • Ca = INCREASE
 • P = N or DECREASE
 • Alk P = N or INCREASE
 • Bone form = n/a
 • Bone resorpt = INCREASE
Renal osteodystrophy:
 • Ca = DECREASE or N
 • P = INCREASE
 • Alk P = INCREASE
 • Bone form = n/a
 • Bone resorpt = n/a
Metastases:
 • Ca = INCREASE
 • P = INCREASE
 • Alk P = INCREASE
 • Bone form = n/a
 • Bone resorpt = INCREASE
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11
Q

Explain why the biochemical investigations include Corrected Ca2+?

A

The corrected Ca2+ considers the Ca2+ bound to albumin

A blood alkalosis forces Ca2+ to bind to albumin
• e.g. hyperventilating patient will have alkalotic blood & thus less free Ca2+

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12
Q

Whats the predominant tole of PTH and clinically relevant points?

A

Predominant role:
• minute-by-minute regulation of [Ca2+]

Clinically relevant points:
 • 84aa peptide – only N1-34 are active
 • Mg2+-dependant
 • T1/2 = 8 minutes
 • PTH receptor is activated by PTHrP
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13
Q

Explain the PTH/[Ca2+] suppression graph

A

The Parathyroid gland monitors serum [Ca2+] via. calcium-sensing receptors

The PTH/[Ca2+] suppression graph is SIGMOID shape (one-note!):
o Minimum – even at high [Ca2+], there is still a base-line PTH secretion.
o Set-point (Ca2+) – the point of HALF-maximal suppression of PTH. So, small changes in [Ca2+] precipitate large PTH changes.
o Note that some people have a physiologically high minimum etc.

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14
Q

Main PTH actions?

A

(1) Drive Ca2+ ABSORPTION in the DCT of kidneys
• via. TRPV5/6

(2) Bone REABSORPTION
• through the RANK system

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15
Q

Who does 1o HPT mostly affect and the causes?

A

50s, females 3:1 males

Causes:
• Parathyroid adenoma - 80% (normally just ONE gland affected)
• Parathyroid hyperplasia - 20%
• Parathyroid cancer - <1%
• Familial syndromes - rare (all 4 glands may be affected)

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16
Q

What is the diagnosis of 1o HPT and the clinical features?

A

Diagnosis:
• ELEVATED total/ionised Ca2+ w. PTH levels frankly ELEVATED OR in the upper normal range
•i.e. hypercalcaemia with PTH in upper normal range (NOT physiologically normal)

Clinical features:

Stones, moans &amp; abdominal groans!!
 • fractures (due to bone reabsorption)
 • renal colic = nephrocalcinosis = CRF
 • dyspepsia, pancreatitis, constipation, nausea, anorexia
 • depression, impaired [ ], coma
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17
Q

Explain how high serum Ca2+ causes diuresis in 1o HPT

A

 High [Ca2+] SHUTS DOWN the K-channels as K+ is recycled to reabsorb calcium normally via paracellular reabsorption

 This results in a dehydration as less Na reabsorbed

 Frusemide has the same mechanism of action of inhibiting the potassium channels.
o Loop diuretic – Triple transporter inhibitor.

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18
Q

What risks does chronically high PTH cause?

What does 1o HPT result in?

A

Chronically high PTH also increases:
• stone risk
• cortical bone reabsorption
• fracture risk

Primary HPT results in:
• HIGH serum calcium (via. absorption from bone/gut)

  • LOW serum phosphate (excreted in PCT); creatinine may also be elevated.
  • PTH in upper half of normal range OR elevated
  • Increased urine Ca2+ excretion
19
Q

How does Vit D work?•

A

 Vit-D Binding Protein (DBP)
 T1/2 3 days
 Filtered by kidneys

TRPV6 is activated by 1, 25(OH)Vit-D to reabsorb Ca2+:
o Reabsorption via channel or paracellular.
o 20-60% via the duodenum, jejunum and colon
o Mostly passive but up to 40% active transport.

20
Q

Main actions of Vit D?

A

Main action of GUT:
 Reabsorb Ca2+ and PO43- in the gut
– TRPV6
– calbindin

 Acts on osteoblasts to increase formation of clasts through RANKL

 Increase osteoblast differentiation

 Facilitate PTH action in DCT
– TRPV6
– calbindin

 Feedbacks on parathyroid to reduce PTH secretion.

21
Q

What is defined as Vit D deficiency?

A

Muscle function is optimal at >70nmol/L

SO less than 50nmol/L = deficient

22
Q

Define Rickets, giving its symptoms and signs

A

Defective mineralisation of the cartilaginous growth plate (BEFORE A LOW Ca2+) due to Vit. D deficiency!

Symptoms:
 (axial) bone pain
 proximal myopathy.

Signs:
 age-dependant deformity
 myopathy,
 Hypotonia
 short stature, tenderness on percussion
o Chvostek’s and Trousseau’s signs on inspection.

23
Q

Causes of Rickets?

A

Dietary

GI
• malabsorption
• pancreatic/liver disturbance
• drugs (phenytoin, phenobarbitone, orlistat

Renal
• CRF

Rare hereditary
• VitD-dependant rickets

24
Q

Biochemistry signs of Rickets?

A 
Serum:
 • Ca2+ = N/LOW
 • PO43- = N/LOW
 • ALP = HIGH
 • Calcitriol = LOW
 • PTH = HIGH (compensatory)

Urine
• PO43- = HIGH
• glycosuria, aminoaciduria, high PTH, proteinuria

25
Q

What do PTH and FGF-23 cause in regards to PO43-?

A

PTH
• PO43- LOSS

FGF-23
• PO43- LOSS
• Inhibits CALCITRIOL formation

26
Q

Explain how PTH and FGF-23 function in regards to PO43-?

A

FGF-23 and PTH inhibit the phosphate/Na co-transporters and so result in phosphate loss:
o FGF-23 inhibits NPT2a and NPT2c.
o PTH inhibits NPT2a

 Phosphate is fully filtered and only reabsorbed in the PCT.

 FGF-23 is produced by osteoblasts and causes phosphate loss BUT also INHIBITS activation of VitD by 1-alpha-hydroxylase

27
Q

How does FGF-23 also lead to OSTEOMALACIA?

A

 Calcium and phosphate is reabsorbed and then PTH secretion is switched off due to high [Ca] –ve feedback.

 Osteoblasts produces FGF-23 to switch off phosphate reabsorption (as phosphate higher too) but FGF-23 also switches off calcitriol formation.

 FGF-23 INHBITS calcitriol formation.

o THIS IS HOW IT ALSO LEADS TO OSTEOMALACIA.

28
Q

Link between Osteomalacia & PO43-?

A

Due to FGF-23, can also get renal PO43- loss when [Ca] & [VitD] levels are NORMAL

Called ‘Isolated’ Hypophosphatemia:
o X-linked hypophosphatemia Rickets
o Autosomal dominant hypophosphatemia rickets (ADRR)
o Oncogenic osteomalacia

All 3 of these lead to HIGH FGF-23

Kidney PCT damage can lead to hypophosphatemia & phosphaturia

29
Q

Define and state the causes of osteoporosis?

A

Low bone density!

High turnover
• increased bone resorption&raquo_space; bone formation
• e.g. oestrogen deficiency

Low turnover
• decreased bone formation&raquo_space; bone resorption
• e.g. liver disease

Increase bone resorption & decreased bone formation
• e.g. glucocorticoids

30
Q

Explain how oestrogen deficiency from menopause can cause bone loss

A

o Increased number of remodelling units

o Causes remodelling imbalance – increased resorption compared to formation

o Remodelling errors (deeper and more resorption pits) lead to trabecular perforation and cortical excess excavation

o Decreased osteocyte sensing.

31
Q

Early osteoporosis diagnosis?

A

 Cancellous bone loss is marked EARLY in the menopause

 Osteoporosis results in increased fracture risks.

32
Q

Explain how biochemistry is used to diagnose osteoporosis

A

Used to EXCLUDE other causes
• serum biochemistry should be NORMAL if osteoporosis

 Check for VitD deficiency.
 Check for 2o endocrine causes – e.g. P-HPT (PTH high), P-HT (T3 high), hypogonadism.
 Exclude multiple myeloma.
 Check for high urine calcium

33
Q

What is the main tool used to assess for osteoporosis and explain this

A

Bone Density - BMD
• represents 70% of total risk

 DEXA scans – measures differences in densities between 2 different materials

 Definition of osteoporosis is based on BMD – T-score: <=-2.5 = osteoporosis.
• 1 S.D. reduction = 2.5x increase in fracture risk.

We measure:
• vertebral (commonest fractures, measures cancellous bone which is metabolic bone so responds fastest to treatment)
AND
• hip (second most common) BMDs

 FRAX – Fracture Risk Assessment Tool
– uses BMD
(Ludley for equation!!)

34
Q

What else can be used besides BMD for osteoporosis diagnosis?

A

BONE MARKERS!

Unlike BMD, bone markers are DYNAMIC

 Formation markers:
• P1NP – Procollagen type 1 N-terminal Propeptide
 In production of collagen (2112), extension polypeptides (P1NP) are cleaved

 Resorption markers:
 • Serum CTX 
  – Cross-linked C-telopeptides.
 • Urine NTX 
  – Cross-linked N-telopeptides
    3 hydroxylysine molecules condense out to form a pyridinium ring linkage on resorption of bone
35
Q

Which bone marker is used to monitor osteoporosis treatment?

BUT what are the problems?

A

Resorption markers!!

Monitoring response to treatment with anti-resorptive drugs:
o Bone reabsorption markers fall in 4-6 weeks
o Expect a 50% drop of urine NTx by 3 months

Problems though with cross-links:
  Hard to reproduce.
  Positive association with age anyway.
  Need to correct for creatinine.
  Diurnal variation in urine markers
36
Q

Which bone marker is used clinically?

A 
ALKALINE PHOSPHATASE (ALP)
 • Formation Marker

Used in the diagnosis/monitoring of:
• Pagets
• Osteomalacia
• Bone metastasis

37
Q

Which ALP is used clinically as a formation marker?

A

BSAP – Bone-Specific Alkaline Phosphatase:

• Types – tissue-specific (bone) form of ALP.

• Roles – essential for
mineralisation of bone & regulates concentrations of phosphate.

• Uses – T1/2 40 hours. Increased in Paget’s, osteomalacia, bone metastasis, HPT, HT.

 NOTE that ALP varies with age (younger people have more)

38
Q

How is P1NP being used as a formation marked?

A

As predictor of response to anabolic treatments

• e.g. PTH treatment

39
Q

Explain how CKD leads to bone issues

A

Chronic Kidney Disease:

o Skeletal remodelling disorders caused by CKD contribute to vascular calcification (extra-skeletal deposition)

o The disorders in mineral metabolism with CKD are a main reason to mortality from CKD

Pathophysiology:
– impairs skeletal anabolism
– decreases osteoblast function
– decreases bone formation.

40
Q

Explain the biochemistry & pathway of Renal Osteodystrophy

A

Biochemistry:
– increased [phosphate]
– reduced calcitriol

 Think, kidney failure so less calcitriol and nephron loss so less phosphate filtrated into urine

Pathway:
– 2o HPT develops to compensate –> unsuccessful so hypocalcaemia –> parathyroid become autonomous (tertiary hyperparathyroidism) –> hypercalcaemia

There is a progressive hyperplasia of the parathyroids

41
Q

Explain the consequences of Nephron Loss due to CKD

A

(1) Phosphate binds to Ca in serum
• Calcium phosphate crystals are deposited causing extra-skeletal calcifications

(2) Acidosis
• causes demineralisation

(3) Decreased calcitriol
• leads to hypocalcaemia = 2o PTH = increased bone resorption
• also leads to osteomalacia (problem w. mineralisation)

42
Q

What can you get with renal osteodysptropgy?

A

Heterotropic calcification
• bone formation at an abnormal anatomical site, usually in soft tissue
• i.e. in MCP joints

43
Q

Relationship between Renal osteodystrophy and CKD

A

Renal osteodystrophy is a CONSEQUENCE of CKD!

The results of CKD cause the symptoms of osteodystrophy such as heterotopic calcification.

Year 2 - Muscoloskeletal (10 decks)

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